Archived Policies - Surgery


Stem-Cell Transplant for Malignant Astrocytomas and Gliomas

Number:SUR703.042

Effective Date:10-15-2013

End Date:01-14-2015

Coverage:

Coverage of, evaluation for, and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of primary tumors of the brain known as malignant astrocytomas and gliomas, which includes both glioblastoma multiforme and oligodendroglioma, are identified in the grid below.

NOTE: SCT may be known by different terminology and used interchangeably. Hereinafter, SCT will be known as stem-cell support (SCS) throughout the balance of this medical policy.

Allogeneic

Is considered experimental, investigational and unproven for malignant astrocytomas and gliomas.

Autologous

Is considered experimental, investigational and unproven for malignant astrocytomas and gliomas.

Tandem or Triple Stem-Cell Support

Is considered experimental, investigational and unproven for malignant astrocytomas and gliomas.

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven for malignant astrocytomas and gliomas.

Hematopoietic Progenitor Cell Boost (Stem-Cell Boost)

Is considered experimental, investigational and unproven for malignant astrocytomas and gliomas.

Any use of short tandem repeat (STR) markers for the treatment of malignant astrocytomas and gliomas is considered experimental, investigational and unproven.

NOTE:  For detailed, descriptive information on stem-cell support sources, harvesting, storage and infusion, preparative regimens, including high-dose chemotherapy and reduced intensity conditioning, tandem or triple stem-cell support, donor leukocyte infusion, hematopoietic progenitor cell boost (stem-cell boost), and short tandem repeat markers see Medical Policy SUR703.002, “Stem Cells Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information)”.

Description:

Diffuse fibrillary astrocytomas are the most common type of brain tumor in adults. These tumors are classified histologically into three grades of malignancy: grade II astrocytoma, grade III anaplastic astrocytoma, and grade IV glioblastoma multiform. Oligodendrogliomas are diffuse neoplasms that are clinically and biologically most closely related to diffuse fibrillary astrocytomas. However, these tumors generally have better prognoses than diffuse astrocytomas, with mean survival times of 10 years versus two–three years. In addition, oligodendrogliomas appear to be more chemosensitive than other types of astrocytomas. Glioblastoma multiforme is the most malignant stage of astrocytoma, with survival times of less than two years for most patients.

Treatment of primary brain tumors focuses on surgery, either with curative intent or optimal tumor debulking. Surgery may be followed by radiation therapy and/or chemotherapy. Survival after chemoradiotherapy is largely dependent on the extent of residual tumor after surgical debulking. Therefore, tumors that arise in the midline, basal ganglia, or corpus callosum or those arising in the eloquent speech or motor areas of the cortex, which typically cannot be extensively resected, have a particularly poor outcome. Treatment of children younger than 3 years is complicated by the long-term effects of radiation therapy on physical and intellectual function. Therefore, in young children, radiation of the central nervous system (CNS) is avoided whenever possible.

Astrocytomas and gliomas arise from the glial cells. Tumors arising from the neuroepithelium constitute a separate category of malignancies that include CNS  neuroblastoma, medulloblastoma, ependymoblastomas, and pineoblastomas. Collectively these tumors may be referred to as primitive neuroectodermal tumors (PNETs). Ependymomas also arise from the neuroepithelium but, because of their more mature histologic appearance, are not considered a member of the PNET family.

NOTE:  For Primitive Neuroectodermal Tumors (PNET) of the CNS, Ependymoma, and Medulloblastomas, please see Medical Policy SUR703.039.

For additional definitions of evaluations or treatments, and general information other than the specific disease or condition listed in this policy, please see Medical Policy SUR703.002, “Stem Cells Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information).”

Rationale:

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) transplant is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, umbilical cord blood, or bone marrow stem-cells. 

Initially, this policy was based on a conclusion from the Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment in 1994. (1) The evidence available at that time did not demonstrate that this procedure improved health outcomes of adult patients with high-grade glial tumors of the brain when treated with autologous stem-cell support (AuSCS) for astrocytomas and gliomas and other malignancies An initial update of the 1994 TEC Assessment included literature that was reviewed and published through 1999. It noted that although there was much research interest in use of autologous SCT for glioblastoma multiforme due to its uniformly poor prognosis, the published literature was relatively scant, consisting primarily of single-institution case series. The following representative examples were cited:

  • Bouffet and colleagues (2) reported on a series of 22 children and young adults with high-grade gliomas treated with AuSCS. The response rate was 29% with one complete and three partial responses. However, the authors concluded that survival with this procedure was no better than that reported with conventional treatments. 
  • Heideman and colleagues (3) reported on a case series of 13 pediatric patients with bulky disease or recurrent disease treated with SCT plus radiotherapy. While the overall response rate was 31%, the authors similarly concluded that overall survival was no better than conventional treatment regimens. 
  • Finlay and colleagues (4) reported on a 1996 case series of 45 children and young adults with a variety of recurrent CNS tumors, including gliomas, medulloblastomas, ependymomas, and primitive neuroectodermal tumors. Of the 18 patients with high-grade gliomas, the response rate was 29%. The median survival of this group was 12.7 months. Of the five long-term survivors, all had high-grade glioma with minimal residual disease at the time of transplantation. Based in part on these results, the authors recommended aggressive surgical debulking before this procedure is even considered.

Studies focusing on the use of autologous SCT in adults with glioblastoma multiforme reported results similar to those in children, being most successful in those with minimal disease at the time of treatment, with an occasional long-term survivor. (5, 6)

A review by Brandes and colleagues (7) concluded that the high drug doses used in this treatment caused excessive toxicity that was not balanced by a significant improvement in survival. Similarly, Levin and coworkers (8) concluded that it was unclear whether hematopoietic SCT had a role in management of cerebral gliomas. Additional reports on small, uncontrolled series of patients with pontine gliomas (9), recurrent oligodendrogliomas, (10) or those undergoing radiation therapies for high-grade gliomas (11) also did not suggest that this treatment improves survival. In a Phase II study, Abrey and colleagues (12) evaluated hematopoietic stem-cell transplantation in 39 patients with newly diagnosed oligodendroglioma. The authors reported the median follow-up of surviving patients was 80.5 months and with 78 months progression-free survival. The overall survival median had not been reached and 18 patients (46%) had relapsed.

Clinical Guidelines

National Comprehensive Cancer Network (NCCN) Guidelines:

The 2008 National Comprehensive Cancer Network (NCCN) Guidelines on Central Nervous System Tumors (v.1.2008) do not list hematopoietic SCT as a treatment option for patients with astrocytomas or gliomas. (13)

National Cancer Institute (NCI) Clinical Trials Database (PDQ®)

A search of the National Cancer Institute Physician Data Query (PDQ) Clinical Trials Database, found one ongoing, but not recruiting, phase II/III trial to determine if stem-cell transplant for newly diagnosed high-risk central nervous system tumors (including glioblastoma multiforme and high-grade astrocytoma) increases overall survival. Two other trials have been completed.

Additional Infusion Treatments for Astrocytomas and Gliomas

Allogeneic, tandem or triple SCT and donor leukocyte infusion (DLI) for astrocytomas and gliomas is considered experimental, investigational and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

2013 Update

A search of peer reviewed literature through October 2012 was conducted. The following is a summary of the key literature to date.

A nonrandomized study compared survival outcomes of 27 children (age, 0.4–22 years) with recurrent malignant astrocytomas who underwent myeloablative chemotherapy and AuSCS with outcomes in a matched historical cohort (n=56) that received standard chemotherapy regimens following tumor recurrence. (14) Among the 27 children who received myeloablative chemotherapy and AuSCS, 5 (18%) succumbed to treatment-related toxicities within approximately 2 months of transplantation, 17 (63%) had disease progression, while 5 survived and were alive a median of 11 years (range: 8–13 years) after transplantation. Overall survival rates at 4 years were 40 ± 14% for transplant patients versus 7 ± 4% with conventional chemotherapy (p=0.018, hazard ratio [HR]: 1.9; 95% confidence interval [CI]: 1.1–3.2). The results of this study suggest myeloablative chemotherapy with AuSCS can produce long-term survival among children with recurrent malignant astrocytoma. However, lack of a contemporaneous treatment comparison group precludes conclusions as to the relative efficacy of this approach. A comprehensive review article identified in the literature search did not report any evidence for the role of HSCT in this disease. (15)

Additional Infusion Treatments for Malignant Astrocytomas and Gliomas Using Hematopoietic Progenitor Cell (HPC) Boost or Stem-Cell Boost (SCB)

As with DLI, HPC Boost has a positive response rate for relapse following AlloSCS. (16) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. However, the data is insufficient for the use of HPC Boost following AlloSCS for treatment of non-hematological malignancies to lessen post-transplant graft failures. (16, 17, 18, 19)

Short Tandem Repeat (STR) Markers

Following SCS therapy, it is important to determine whether the new blood forming system is of the donor or the recipient, based upon the proportion of donor and recipient cells. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (20, 21) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of malignant astrocytomas and gliomas, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (20, 21, 22, 23, 24, 25)

Clinical Guidelines

National Comprehensive Cancer Network (NCCN) Guidelines

The 2012 NCCN Guidelines on Central Nervous System Tumors (v.2.2012) do not list hematopoietic stem cell transplantation as a treatment option for patients with astrocytomas or gliomas. (26)

National Cancer Institute Physician Data Query (PDQ) Clinical Trials Database

A search in November 2012 did not find an active clinical trial of HSCT for any central nervous system tumors addressed in this policy, including glioblastoma multiforme and gliosarcoma.

Summary

The data on the use of autologous hematopoietic stem-cell transplantation for malignant astrocytomas and gliomas, consisting of case series, has, in general, shown no survival benefit compared to conventional therapy with increased treatment-related toxicity. Based on a search of peer reviewed literature, through October 2012, there were no new clinical trial publications or any additional information that would change our coverage position; therefore, AuSCS, allogeneic stem-cell transplant, tandem or triple stem-cell transplant and DLI remain experimental, investigational and unproven for the treatment of malignant astrocytomas and gliomas, which includes both glioblastoma multiforme and oligodendroglioma.

Based on a search of scientific literature in the MedLine database through March 2013, HPC boost to reduce the graft failure process and STR markers to monitor engraftment chimerism for the treatment of malignant astrocytomas and gliomas are considered experimental, investigational, and unproven due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

None

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Experimental, Investigational and Unproven for all codes

ICD-9 Procedure Codes

41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79

ICD-10 Diagnosis Codes

Experimental, Investigational and Unproven for all codes

ICD-10 Procedure Codes

30230G0, 30230G1, 30233G0, 30233G1, 30240G0, 30240G1, 30243G0, 30243G1, 30250G0, 30250G0, 30250G1, 30253G0, 30253G1, 30260G0, 30260G1, 30263G0, 30263G1, 3E03005, 3E03305, 3E04005, 3E04305, 3E05005, 3E05305, 3E06005, 3E06305, 6A550Z2, 6A551Z2, 6A550ZT, 6A550ZV, 6A551ZT, 6A551ZV


Medicare Coverage:

The information contained in this section is for informational purposes only.  HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov.

References:

  1. HDC/AUSCS for High Grade Glial Tumors of the Brain in Adults. Chicago, Illinois: Blue Cross Blue Shield Association Technology Evaluation Center (TEC) Assessment Program (1994) 9(34):1-10.
  2. Bouffet, E., Mottolese, C., et al. Etoposide and thiotepa followed by ABMT (autologous bone marrow transplantation) in children and young adults with high-grade gliomas. European Journal of Cancer (1997) 33(1):91-5.
  3. Heideman, R.L., Douglass, E.C., et al. High-dose chemotherapy and autologous bone marrow rescue followed by interstitial and external-beam radiotherapy in newly diagnosed pediatric malignant gliomas. Journal of Clinical Oncology (1993) 11(8):1458-65.
  4. Finlay, J.L., Goldman, S., et al. Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children’s Cancer Group. Journal of Clinical Oncology (1996) 14(9):2495-503.
  5. Linassier, C., Benboubker, L., et al.  High-dose BCNU with ABMT followed by radiation therapy in the treatment of supratentorial glioblastoma multiforme.  Bone Marrow Transplant (1996) 18(suppl 1): S69-72.
  6. Fernandez-Hidalgo, O.A., Vanaclocha, V., et al.  High-dose BCNU and autologous progenitor cell transplantation given with intra-arterial cisplatinum and simultaneous radiotherapy in the treatment of high-grade gliomas: benefit for selected patients.  Bone Marrow Transplant (1996) 18(1):143-9.
  7. Brandes, A.A., Palmisano, V., et al. High-dose chemotherapy with bone marrow rescue for high-grade gliomas in adults. Cancer Investigation (2001) 19(1):41-8.
  8. Levin, V.A., Leibel, S.A., et al.  Neoplasms of the central nervous system. In: Cancer: Principles and Practice of Oncology, ed 6. VT DeVita, Jr, S Hellman, and SA Rosenberg, eds. Philadelphia: Lippincott Williams and Wilkins; (2001) 2100-60.
  9. Bouffet, E., Raquin, M., et al. Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer (2000) 88(3):685-92.
  10. Cairncross, G., Swinnen, L., et al. Myeloablative chemotherapy for recurrent aggressive oligodendroglioma. Neuro-oncology (2000) 2(2):114-9.
  11. Jakacki, R.I., Siffert, J., et al. Dose-intensive, time-compressed procarbazine, CCNU, vincristine (PCV) with peripheral blood stem cell support and concurrent radiation in patients with newly diagnosed high-grade gliomas. Journal of Neuro-oncology (1999) 44(1):77-83.
  12. Abrey, L.E., Childs, B.H., et al.  High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma: long-term follow-up. Neuro Oncology (2006) 8(2):183-8.
  13. NCCN – Central Nervous System Cancers – NCCN Clinical Practice Guidelines in Oncology, Version.1.2008. National Comprehensive Cancer Network available at <www.nccn.org> (accessed on - 2008 July 1). 
  14. Finlay JL, Dhall G, Boyett JM et al. Myeloablative chemotherapy with autologous bone marrow rescue in children and adolescents with recurrent malignant astrocytoma: outcome compared with conventional chemotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer 2008; 51(6):806-11.
  15. Ricard D, Idbaih A, Ducray F et al. Primary brain tumours in adults. Lancet 2012; 379(9830):1984-96.
  16. ACS – Stem Cell Transplant (Peripheral Blood, Bone Marrow, and Cord Blood Transplants) (2013). American Cancer Society. Available at <http://www.cancer.org> (accessed – 2013 April 15).
  17. Slatter, M.A., Bhattacharya, A., et al. Outcome of boost hematopoietic stem cell transplant for decreased donor chimerism or graft dysfunction in primary immunodeficiency. Bone Marrow Transplantation (2005) 35:683-9.
  18. Larocca, A., Piaggio, G., et al. A boost of CD35+-selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation. The Hematology Journal (2006) 91(7):935-40.
  19. NIH – Marrsson, J., Ringden, O., et al. Graft failure after allogeneic hematopoietic cell transplantation. Biology and Blood Marrow Transplant (2008 January) 14(Supplement 1):165-70. National Institutes of Health Public Access. Available at <http://www.nih.gov> (accessed – 2013 April 15).
  20. Borrill, V., Schlaphoff, T., et al. The use of short tandem repeat polymorphisms for monitoring chimerism follow bone marrow transplantation: a short report. Hematology (2008 August) 13(4):210-4.
  21. Crow, J., Youens, K., et al. Donor cell leukemia in umbilical cord blood transplant patients: a case study and literature review highlighting the importance of molecular engraftment analysis. Journal of Molecular Diagnostics (2010 July) 12(4):530-7.
  22. Park, M., Koh, K.N., et al. Clinical implications of chimerism after allogeneic hematopoietic stem-cell transplantation in children with non-malignant diseases. Korean Journal of Hematology (2011 December) 46(4):258-64.
  23. Odriozola, A., Riancho, J.A., et al. Evaluation of the sensitivity of two recently developed STR multiplexes for the analysis of chimerism after hematopoietic stem-cell transplantation. International Journal of Immunogenetics (2013 April) 40(2):88-92.
  24. Lawler, M., Crampe, M., et al. The EuroChimerism concept for standardized approach to chimerism analysis after allogeneic stem-cell transplantation. Leukemia (2012 August) 26(8):1821-8.
  25. Tilanus, M.G. Short tandem repeat markers in diagnostics: what’s in a repeat? Leukemia (2006 August) 20(8):1353-55. Available at <http:www.nature.com> (accessed – 2013 April 22).
  26. NCCN – Central Nervous System Cancers – NCCN Clinical Practice Guidelines in Oncology, Version.2.2128. National Comprehensive Cancer Network available at <www.nccn.org> (accessed on - 2012 November 7). 
  27. Autologous Hematopoietic Stem-Cell Transplantation for Malignant Astrocytomas and Gliomas. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 September) Therapy 8.01.31.
  28. Donor Leukocyte Infusion for Hematologic Malignancies Treated with an Allogeneic Stem Cell Transplant. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 May) Medicine: 2.03.03.

Policy History:

10/15/2013      Document updated with literature review. The following was added: 1) Donor leukocyte infusion and hematopoietic progenitor cell boost are considered experimental, investigational and unproven; and 2) Any use of short tandem repeat (STR) markers for the treatment of malignant astrocytomas and gliomas is considered experimental, investigational and unproven. Otherwise, coverage unchanged. Description and Rationale significantly revised. Document title changed from Stem-Cell Transplant for Astrocytomas and Gliomas.

4/1/2010          New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem Cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies.  Stem cell transplant remains experimental, investigational and unproved when used to treat astrocytomas and gliomas.

[NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information):

  • Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies;
  • Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies;
  • Cord Blood as a Source of Stem Cells;
  • Donor Leukocyte Infusion (DLI); and
  • Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies.

Archived Document(s):

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